Alpha-carboxamidomethylaminocarboxamides



United States Patent 3,293,294 a-CARBOXAMIDOMETHYLAMINO- CARBOXAMIDESDull Shederic Allen, Jr., Dobbs Ferry, and Edward Rudolph Ruso, Nanuet,N.Y., and Sidney A. Frankel, Edison, N.J., assignors to AmericanCyanamid Company, Stamford, Conn., a corporation of Maine No Drawing.Filed Sept. 28, 1965, Ser. No. 491,032 3 Claims. (Cl. 260-558) Thisapplication is a continuation-in-part of our copending applicationSerial No. 303,410, filed August 20, 1963.

This invention relates to new intermediates useful in a process ofpreparing 3 disubstituted 2,6 piperazinediones.

The novel intermediate compounds of the present invention may berepresented by the following formula:

wherein R and R are carboxamido; R is lower alkyl and R is phenyl, orhalophenyl and acid addition salts thereof.

In the above formula, the term lower alkyl is intended to embracehydrocarbon radicals having 1 to 6 carbon atoms such as, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like. Theterm halophenyl is intended to include chlorophenyl, bromophenyl,fluorophenyl and iodophenyl. The present compounds when treated with anacid will form acid addition salts such as hydrochloride, hydrobromide,sulfate, nitrate, etc.

The a-carboxamiclomethylaminocarboxamide interme-.

diates of this invention are in general crystalline solids which aresomewhat soluble in the usual organic solvents and relatively insolublein water.

The a-carboxamidomethylaminocarboxamide intermediates of thisinventionmay be prepared from a-cyanomethylaminonitrile anda-carboxamidomethylaminonitrile intermediates (i.e., those intermediateswherein R would be cyano and R would be cyano or carboxamido) byconventional hydrolysis. Usually the starting intermediate is dissolvedin concentrated sulfuric acid and after a short time the sulfuric acidsolution is poured into cracked ice causing the product to separate. Thecrude product may be purified by conventional methods ofcrystallization.

The a-carboxamidomethylaminocarboxamide intermediates of the presentinvention may be cyclized to the corresponding 3-lower alkyl-3-phenyl orhalophenyl 2,6- piperazinediones by heating the starting intermediatesto a temperature within the range of from about 180 C. to about 250 C.for a period of time from about /2 to about 4 hours. Usually a solventis not necessary since the starting compound melts at the elevatedtemperature and cyclizes with evolution of ammonia. The piperazinedionesmay also be prepared by treating the present intermediates with analkali metal oxide in an anhydrous solvent at a temperature within therange of from about to about 120 C. for a period of time of from about/2 hour to 24 hours.

A number of the intermediates described hereinafter in the examples areuseful in an improved process for preparing 3-lower alkyl-3-mononucleararyl-2,6-piperazinediones as described and claimed in our copendingapplication Serial No. 303,411 filed August 20, 1963.

The 3-lower alkyl-3-phenyl or halophenyl 2,6-piperazinediones preparedfrom the intermediates of the present invention have valuable centralnervous system depressant 3,293,294 Patented Dec. 20, 1966 ice activity.For example, the compound 3-ethyl-3-phenyl- 2,6-piperazinedione whentested in mice shows a reduction of spontaneous motor activity moreeffective than that produced by meprobamate (a recognized tranquilizer).In a similar test the above compound when compared with phenobarbital (arecognized hypnotic) shows a tranquilizing action whereas phenobarbitalexhibits no such action. In general, the 3-lower alkyl-3-phenyl orhalophenyl-2,6-piperazinediones when tested in mice show the activity ofhypnotics, tranquilizers and muscle relaxant properties in warm-bloodedanimals.

The following examples illustrate in greater detail the preparation of anumber of intermediates and their conversion to 3-lower alkyl-3-phenylor halophenyl-2,6- piperazinediones.

EXAMPLE I Preparation of 2-[(a-cyano-a-ethylbenzyl)amino] acelamide Amixture of 62 ml. of anhydrous methanol, 16.6 g. (0.124 mole) ofpropiophenone, 6.4 g. (0.130 mole) of granular sodium cyanide and 17.7g. of 85% glycinamide hydrochloride (0.136 mole) is stirred for 18 hoursat 25 30 C. in a closed flask. The mixture is heated at 60 C. for 6hours, then cooled to 30 C. and filtered to remove inorganic insolubles.Concentration of the filtrate under reduced pressure gives an ambercolored oily residue to which is added 175 ml. of benzene. The mixtureis filtered to remove insolubles and the filtrate is concentrated underreduced pressure. To the oily residue is added ml. of ether and 75 ml.of petroleum ether. After stirring for one hour the product is separated'by filtration to give 20.1 g. (75% of theory) of pale tan crystals,melting point 7983 C. A sample from a similar experiment isrecrystallized repeatedly frorn benzene-petroleum ether to give acolorless solid, melting point 8789 C.

EXAMPLE II Preparation of 2- (carbelhoxymethyl) amino]-2-phenylbutyronitrile hydrochloride A mixture of 30.7 g. (0.22 mole) ofethyl glycinate hydrochloride, 10.6 g. (0.21 mole) of granular sodiumcyanide, 26.8 g. (0.20 mole) of propiophenone (melting point 192l C.) in100 ml. of anhydrous methanol is stirred for 22 hours at 2530 C. in aclosed flask. The mixture is heated at 60-62 C. for 6 hours, then cooledto 25 C. and filtered to remove inorganic insolubles. Concentration ofthe filtrate under reduced pressure gives a yellow oily residue to whichis added 200 ml. of ether. The mixture is filtered and the filtrate istreated with excessanhydrous hydrogen chloride. A colorless crystallinesolid is separated by filtration and amounts to 50.7 g. (88% of theory),melting point 11l.5-115.5 C.

EXAMPLE III Preparation of 2[ (carbamoylmethyl) amino1-2-phenylbmyramide A solution of 53 g. (0.25 mole) ofZ-cyanomethylamino-2-phenylbutyronitrile in 100 ml. of reagent gradeconcentrated sulfuric acid is stirred for 2 hours at 2030 C. Thesolution is poured into -a stirred mixture of 500 ml. of chloroform and500 g. of ice. The mixture is made alkaline (pH 8) by the addition ofconcentrated ammonium hydroxide and the product is separated byfiltration, washed with water and dried at A total of 32 g. of tancolored prisms, melting point l59-162 is obtained.

3 EXAMPLE IV Preparation of 2-[ (a-cyano-a-methylbenzyl) amino] acetamide A mixture of 62 ml. of anhydrous methanol, 14.9 g. (0.124 mole) ofacetophenone, 6.7 g. (0.137 mole) of granular sodium cyanide and 19.1 g.of glycinamide hydrochloride (0.173 mole) is stirred for 18 hours at 2530 C. in a closed flask. The mixture is heated at 60 C. for 6 hours,then cooled to 30 C. and filtered to remove inorganic insolu-bles.Concentration of the filtrate under reduced pressure gives an oil towhich is added 400 ml. of isopropyl alcohol. The mixture is filtered andthe filtrate is concentrated under reduced pressure to give an oilyresidue which on treatment with ether-petroleum ether produces a solidcrude product. Several crystalliza tions of this material formbenzene-petroleum ether gives 5.0 g. of off-white solids, melting point8485 C.

EXAMPLE V Preparation of 2- (ot-cyano-oz-n-amylbenzyl) amino]- acetamide35.3 g. (0.200 mole) hexanephenone, 31.2 g. (24.3 g. real; 0.220 mole)glycinamide hydrochloride, 10.3 g. (0.210 mole) sodium cyanide and 150ml. reagent methanol are charged to a 450 ml. Parr pressure bottlecontaining a magnetic stirring bar. The bottle is sealed by clamping arubber stopper (through which a thermometer has been inserted) to thebottle. The mixture is stirred overnight at (16-20 hours) roomtemperature and then at 60-65 C. for 6 hours. The reaction mix-ture iscooled to room temperature, the bottle opened and the contents filtered.The filter cake is washed with three 50 ml. portions of methanol. Thefiltrate and washes are combined and concentrated by evaporation to amixture of an oil and a small amount of solid. The residue is treatedwith about 200 ml. of benzene and a small amount of undissolved solidremoved by filtration. The filtrate is concentrated on a rotaryevaporator to a light amber colored oil, which is dissolved in about 100ml. of diethyl ether. The ether solution is stirred vigorously anddiluted slowly with 300 ml. of petroleum ether 3060) to a persistenthaze. Within a few minutes a tan solid begins to separate. The mixtureis stirred at room temperature overnight. The product is collected byfiltration, washed with three 100 ml. portions of petroleum ether(30-60), and air dried to a constant weight of 29.5 g. (57.0% The crudeproduct, which is not further purified, melts at 88- 90 C.

EXAMPLE VI Preparation of Z-amino-Z-phenyl prop'ionitrile hydrochlorideA solution of 11.9 g. (0.700 mole) anhydrous ammonia in 100 ml. ofmethanol is placed in a 450 ml. Parr pressure bottle containing amagnetic stirrer bar. To the bottle is added 42.0 g. (0.350 mole)aceto-phenone, 20.6 g. (0.385 mole) ammonium chloride, 18.0 g. (0.368mole) sodium cyanide and 50 ml. methanol and the bottle sealed with arubber stopper, through which a thermometer is inserted. The mixture isstirred for 1620 hours at room temperature and then at 60 65 C. for 6hours. After cooling to room temperature the bottle is opened and thecontents filtered. The cake is washed with three 50 ml. portions ofmethanol. The combined filtrate and washes are concentrated on a rotaryevaporator to an amber oil. The oil is treated with about 500 ml. ofdiethyl ether and a small amount of undissolved solid is removed byfiltration. The filtrate is decolorized with activated charcoal,filtered and gased with anhydrous hydrogen chloride. A white solidseparates almost immediately. The product is collected by filtration,washed with three 100 ml. portions of diethyl ether and air dried to aconstant weight of 44.8 g. (70%). The product melts at 110112.5 (ananalytically pure sample melted at 113113.5 C.).

4 EXAMPLE vn Preparation of Z-amino-Z-phenyl butyronitrile hydrochlorideA solution of 11.9 g. (0.700 mole) of ammonia in 100 ml. of methanol ischarged to a 450 ml. Parr pressure bottle containing a magnetic stirrerbar. To this is added 47.0 g. (0.350 mole) propiophenone, 20.6 g. (0.385mole) ammonium chloride, 18.0 g. (0.368 mole) sodium cyanide and 50 ml.methanol and the bottle sealed with a rubber stopper, through which athermometer has been inserted. The mixture is stirred at roomtemperature overnight (16 20 hours) and then at 60 C. (13) for about 6hours. After cooling to room temperature the bottle is opened and thecontents filtered. The cake is Washed with three 50 ml. portions ofmethanol. The combined filtrate and washes are concentrated under an airdraft to an amber oil. The residue is treated with about 500 ml. ofdiethyl ether. A very small amount of solid remains undissolved. Themixture is treated with activated charcoal and filtered. The cake iswashed with three 50 ml. portions of ether.

The combined filtrate and washes are gassed with anhydrous hydrogenchloride. A white solid precipitated immediately, is collected byfiltration, and washed with three ml. portions of ether. The product isair dried to a constant weight of 58.1 g. (84.5%) and melts at 128 C.(analytically pure material is reported to melt at 129-130 0.).

EXAMPLE VIII Preparation of 2-amin0-2-phenylbutyronitrile hydrochloride107 g. (2.00 moles) of ammonium chloride, 245 ml. (3.68 moles) of 28%aqueous ammonia, 244 g. (1.82 moles) of propiophenone, 550 ml. ofethanol, 118 g. (1.82 moles) of potassium cyanide and 440 ml. of waterare charged into a reaction flask in the above order. The flask issealed, the mixture stirred at room temperature for about one hour andthen heated at 6065 C. overnight. The reaction mixture is cooled tobelow 20 C., the flask is opened, 15-20 g. of activated charcoal isadded and the slurry is stirred for one-half hour and filtered throughdiatomaceous earth; the filter cake is washed with four 100 ml. portionsof ethanol. The filtrate and washes are combined and concentrated underreduced pressure on a steam bath to a mixture of oil and solid. Aboutone liter of benzene is added and the mixture again concentrated to amixture of oil and solid; this process is repeated with an additionalone liter of benzene. A quantity of 1.5 liters of benzene is added,500-750 ml. of solvent is removed by distillation and 20 g. of activatedcharcoal is adedd to the residue. This mixture is stirred at 4050 C. for15 minutes, filtered through diatomaceous earth and the filter cakewashed with three 75 ml. portions of benzene. The combined filtrate andwashes are dried over magnesium sulfate and activated charcoal for aboutan hour and filtered through diatomaceous earth. Anhydrous hydrogenchloride is passed into the filtrate for one half hour; a tan solidseparated within 23 minutes. This crude product is collected, slurriedin 750 ml. of anhydrous diethyl ether, filtered and the cake washed withthree 200 ml. portions of diethyl ether. After air drying overnight, theproduct weighs 115 g. (43%) and melted at 126-129 C., analytically purematerial melts at 129-130 C.

EXAMPLE IX Preparation of Z-amino-Z-phenylvaleronitrile hydrochloride84.5 g. (1.58 moles) of ammonium chloride, ml. (2.86 moles) ofconcentrated ammonium hydroxide, 214 ml. (211 g., 1.43 moles) ofn-butyrophenone, 430 ml. of ethanol, 93.0 g. (1.43 moles) of potassiumcyanide and 350 ml. of Water are added to a reaction flask in the aboveorder, the flask is sealed, the mixture is stirred at room temperaturefor one hour and then at 60'65 C. for about 18-20 hours. After coolingto less than 20 C., the flask is opened in a hood, the mixture isfiltered through diatomaceous earth and the cake is washed with three100 ml. portions of ethanol. Washes and filtrate are combined andconcentrated at reduced pressure on a steam bath to yield an oily solid.This residue is dried by addition of one liter of benzene to the residueand concentration of the mixture to an oily solid. The solid is taken upin 1.5 liters of benzene, 20 g. of activated carbon is added and themixture is stirred at room temperature for /2 hour. Solids are removedby filtration through diatomaceous earth and the cake is washed withfour 50 ml. portions of benzene. The filtrate and washes are com-binedand concentrated on a steam bath at atmospheric pressure until the vaportemperature reached 81 C. Then the distillate comes over clear (about 1liter of benzene has distilled). This residue is again treated with 500ml. of benzene and an additional 200- 250 ml. of benzene is removed bydistillation. The residual benzene solution 'is dried for one hour overmagnesium sulfate, treated with activated carbon, filtered throughdiatomaceous earth and the cake washed with three 50 ml. portions ofbenzene. The combined filtrate and washes are cooled in an ice-waterbath and treated with anhydrous hydrogen chloride for about /2 hour. Alight tan colored solid precipitates within 45 minutes. The crudeproduct is collected, slurried in 1.50 liters of reagent diethyl etherand insolubles isolated by filtration. The product is washed on thefilter with three 100 ml. portions of ether. After air drying overnight,96.0 g. of product, melting point 124126.5 C. with decomposition isobtained.

EXAMPLE X Preparation of Z-amino-Z-phenyl capronitrile hydrochloride Asolution of the ammonia in 100 ml. of the methanol is charged to a 450ml. Parr pressure bottle containing a magnetic stirrer bar. To this isadded 52.6 g. (0.325 mole) of valerophenone, 11.2 g. (0.657 mole) ofanhydrous ammonia, 19.1 g. (0.357 mole) of ammonium chloride, 15.9 g.(0.325 mole) of sodium cyanide and 50 ml. of methanol and the bottlesealed with a rubber stopper, through which a thermometer has beeninserted. The mixture is stirred for one hour at room temperature andthen at 6061C. overnight (1618 hours). The mixture is chilled to about15 C., the bottle opened, and the contents filtered. The cake is washedwith three 50 ml. portions of methanol. The filtrate and Washes arecombined and concentrated on a rotary evaporator to a mixture of oil andsolids. The mixture is treated with about 250300 ml. of diethyl ether,5-6 g. of activated charcoal and filtered. The cake is washed with three50 ml. portions of ether. The filtrate and washes are combined andtreated with anhydrous hydrogen chloride. With 12 minutes a dense Whiteprecipitate is formed and 250 ml. portion of ether is added. The productis collected by filtration, washed with ether and air dried to aconstant weight of 55.0 g. (75.5%). The material melts at 123.5 l26 C.and an analytically pure sample at 124.5126 C.

EXAMPLE XI Preparation of 2-amino-Z-phenylcapronitrile hydrochloride 107g. (2.00 moles) of ammonium chloride, 245 ml. (3.68 moles) of 28%aqueous amonia, 295 g. (1.82 moles) of valerophenone, 550 ml. ofethanol, 440 ml, of water and 118 g. (1.82 moles) of potassium cyanideare added to a reaction flask in the above order and the flask is sealedand then heated at 6065 C. for 20 hours. After cooling the dark reactionmixture to less than C., the flask is opened and 25 g. of activatedcharcoal is added. This mixture is stirred at room.temperature for abouta half hour then filtered through diatomaceous earth and the cake iswashed with three 100 ml. portions of ethanol. Filtrate and washes arecombined and concentrated on a steam bath under aspirator vacuum to anoily solid residue. A quantity of 1.5 liters of diethyl ether and 50 g.of activated charcoal are added to the residue and this mixture isstirred at 25 C. for a half hour before it is filtered throughdiatomaceous earth. The cake is washed with four 100 ml. portions ofdiethyl ether. Combined filtrate and Washes are allowed to stand overmagnesium sulfate for an hour, solids are removed and washed with three50 ml. portions of ether. The filtrate and washes are combined, chilledin an ice-acetone bath, and treated with anhydrous hydrogen chloride.The crude hydrochloride precipitated as a tan granular solid Within 34minutes. The solid is collected by filtration and washed with four 100ml. portions of anhydrous diethyl ether. After air drying a total of84.0 g. of product is obtained (melting point 113115.5 C.).

EXAMPLE XII Preparation of 2-cyanomethylamino-2- phenylpropionitrile20.1 g. (0.110 mole) of Z-amino-2-phenylpropionitrile hydrochloride, 150ml. of reagent methanol, 7.6 ml. (ca. 0.100 mole) of 3740% aqueousformaldehyde and 5.14 g. (0.105 mole) of sodium cyanide are charged intoa 450 ml. Parr pressure bottle containing a magnetic stirring bar.stopper, .through which a thermometer has been inserted to the bottle.The mixture is stirred overnight (1620 hours) at room temperature thenat 60 C. (13 C.) for 5 /2 hours. The mixture is cooled to roomtemperature, bottle opened and the contents treated with about 4 g. ofactivated charcoal. The charcoal and insolubles are removed byfiltration and the cake Washed with three 50 ml. portions of methanol.The filtrate and washes are combined and concentrated under an air draftovernight. The residue of oil and solid is treated with 200' ml. ofdiethyl ether and 5 g. of activated charcoal. The mixture is filteredthrough diatomaceous earth. The filter cake is washed with three 50 ml.portions of diethyl ether. The filtrate and Washes are combined andconcentrated on a rotary evaporator to an amber oil. The concentrationis continued until the weight of product remained constant (17.0 g.,92.0%).

EXAMPLE XIII Preparation of 3-ethyl-3-phenyl-2,6-piperazincdione Amixture of 2.01 g. (0.0093 mole) of2-[(a-cyano-aethyl'benzyl)amino]-acetamide (melting point -85 C.) and0.707 g. (0.0131 mole) of sodium methylate in 17 ml. of anhydrousethanol is stirred at 2530 C, for 16 hours. The solvent is evaporatedunder reduced pressure and the residue is dissolved in 17 ml. of Water.The aqueous solution is acidified with 1 ml. of glacial acetic acid and25 drops of concentrated hydrochloric acid, stirred for 1 hour at 25 30C. and then neutralized with dilute ammonium hydroxide. The product isisolated by filtration and amounts to 1.05 g. (52% of theory) of tancrystalline solid, melting point 115 -118 C., undepressed (1161l8 C.) onadmixture with authentic material.

EXAMPLE XIV Preparation of 3-ethyl-3phenyl-2,6-piperazinedione A mixtureof 12.0 g. (0.051 mole) of2-[(carbamoylmethyl)amino]-2-phenylbutyrarnide (melting point 159- 1 62C.) and 3.5 g. (0.065 mole) of sodium methylate in ml. of absolute ethylalcohol is heated at reflux for 2 hours, the system being protected frommoisture by a calcium chloride drying tube. The pale yellow solution iscooled to room temperature and concentrated The bottle is sealed by theclamping of a rubber under reduced pressure. A solution of the oilyresidue in 100 ml. of water is neutralized by the addition of 2.6 ml. ofglacial acetic acid. The product is separated by filtration and amountsto 1.2 g. of theory) of a tan crystallized solid, melting point 113-ll6C., undepressed (melting point 1l21 C.) on admixture with authenticmaterial,

EXAMPLE XV Preparation of 3-ethyl-3phenyl-2,6-piperazinedione A sampleof 2.0 g. of 2-[carbamoylmethyl)amino]-2- phenylbutyramide is heated at200 230" C. for 0.5 hour during which time ammonia is evolved. Thesystem is placed under reduced pressure and heating is continued for anadditional 0.5 hour. The product is cooled at 30 C. and dissolved inacetone. Evaporation of the solvent gives 1.78 g. (96% of theory) ofprisms, melting point 115 -120 C,

EXAMPLE XVI Preparation of 2-[ (carbamoylmethyl) amino] -2- phenylbatyramide A solution of 25 g. (0.12 mole) of[(a-cyano-a-ethylbenzyl)amino]-acetamide in 50 ml. of reagent gradeconcentrated sulfuric acid is stirred for 0.5 hour at 30 C., then pouredslowly into a stirred mixture of 200 ml. chloroform and 200 g. of ice.The mixture is made alkaline (pH 8) by the addition of 185 ml. ofconcentrated ammonium hydroxide. After the addition of 50 ml. ofchloroform the product is separated by filtration, washed with water anddried at 80 C. A total of 19.4 g. (72% of theory) of colorless prismsmelting point 160- 162 C. is obtained.

EXAMPLE XVII Preparation of 2-carbamylmethylamino-2 p henyleapronitrile32.4 g. (0.200 mole) of valerophenone, 23.9 g. (0.216 mole) ofgly-cinamide hydrochloride, 10.3 g. (0.210 mole) of sodium cyanide and100 ml. of methanol are charged into a 450 ml. Parr pressure bottlecontaining a magnetic stirrer bar. The bottle is sealed tightly with arubber stopper through which a thermometer has been inserted. Themixture is stirred overnight at room temperature and then at 60-65 C.for about 6 hours. The reaction mixture is cooled to about 10 C., thebottle opened, and the contents filtered. The cake is washed with three50 ml. portions of methanol. The filtrate and washes are combined andconcentrated under an air draft to a mixture of oil and solid. Theresidue is treated with 200 ml. of benzene, stirred at room temperaturefor one hour and the insoluble solid separated by filtration. The cakeis washed with three 75 ml. portions of benzene. The combined filtrateand washes are concentrated on a rotary evaporator to an amber oil,which is dissolved in 100 ml. of diethyl ether. The ether solution isstirred vigorously while being diluted slowly with 300 ml. of 30-60 C.petroleum ether to a persistent haze. Within /2 hour a thick precipitateof tan solid forms. The solid is collected by filtration, washed wellwith petroleum ether and air dried to a constant weight of 33.6 g.(80.5%) of material which melted at 5662 C. The purified material meltsat 6165 C.

EXAMPLE XVIII Preparation of 2-( [a-cya'no-a-methyl- (p-chlorobenzyl)]amino) acetamide A mixture of 124 ml. of anhydrous methanol, 38.2 g. ofp-chloroacetophenone, 12.8 g. of granular sodium cyanide and 30.0 g. ofglycinamide hydrochloride is stirred for 18 hours at 30 C. in a closedflask. The mixture is heated at 60 C. for 6 hours, then cooled to C. andfiltered to remove inorganic insolubles. Concentra- 8 tion of thefiltrate under reduced pressure gives an oily residue to which is added350 ml. of benzene. The mixture is filtered to remove insol-nbles andthe filtrate is concentrated under reduced pressure. To the oily residueis added 200 ml. of ether. The product is separated by filtration togive 7.0 g. of colorless solids, melting point 87-91 C.

EXAMPLE XIX Preparation of 2-([a-eyano-a-methyl-(mchlorobenzyl) ]amin0)acetamide A mixture of ml. of anhydrous methanol, 38.2 g. ofm-chloroacetophenone, 12.8 g. of granular sodium cyanide and 30.0 g. ofglycinarnide hydrochloride is stirred for 18 hours at 25-30 C. in aclosed flask. The mixture is heated at 60 C. for 6 hours, then cooled to30 C. and filtered to remove inorganic insolubles. Concentrations of thefiltrate under reduced pressure gives an oil to which is added 350 ml.of benzene. The mixture is filtered to removed insolubles and thefiltrate is concentrated under reduced pressure. To the oily residue isadded 200 ml. of ether. The product is separated by filtration to give29.3 g. (50% of theory) of tan crystals, melting point 8490 C.

EXAMPLE XX Preparation 0 f 2 [a-cyano-u-ethyl- (pchlorobenzyl amino)aeetamia'e A mixture of 42 ml. of anhydrous methanol, 20.8 g. ofp-chloropropiophenone, 6.4 g. of granular sodium cyanide and 17.9 g. of84% glycinamide hydrochloride is stirred for 18 hours at 25 -30 C. in aclosed flask. The mixture is heated at 60 C. for 6 hours, then cooled to30 C. and filtered to removed inorganic insolubles. Concentration of thefiltrate under reduced pressure gives amber colored oily residue towhich is added 175 ml. of benzene. The mixture is filtered to removeinsolubles and the filtrate is concentrated under reduced pressure. Tothe oily residue is added 25 ml. of ether and 45 nil. of petroleumether. The product is separated by filtration to give 22.7 g. (73% oftheory) of pale yellow crystals, melting point 72-75 C. A sample from asimilar experiment is recrystallized repeatedly from benzenepetroleumether to give a colorless solid, melting point 83-85 C.

EXAMPLE XXI Preparation of 2-[ (carbam0ylmethyl)amino] -2-p-ehlorophenylpropionamide A solution of 7.6 g. of 2-([a-cyano-a-methyl-(p-chlorobenzyl)]arnino)-aoetamide in 15.0 ml. ofreagent grade concentrated sulfuric acid is stirred for 0.5 hours at 20-30 C., then poured into a stirred mixture of 30 ml. of chloroform and 30ml. of ice. The mixture is made alka- =li11e (pH 8) by the addition of43 ml. of concentrated ammonium hydroxide. The product is separated byfiltration to give 7.9 g. (98% of theory) of colorless solids, meltingpoint 102104 C.

EXAMPLE XXII Preparation of 2-([a-cyan0-a-methyl-(3,4- dichlorobenzyl)]amin0)aoetamide A mixture of 25 ml. of anhydrous methanol, 11.7 g. of3', 4-dichloroacetophinone, 3.2 g. of granular sodium cyanide and 9.0 g.of 84% glycinamide hydrochloride is stirred for 18 hours at 25-30 C. ina closed flask. The mixture is heated at 60 C. for 6 hours, then cooledto 30 C. and fitltered. Concentration of the filtrate under pressuregives an oily residue to which is added 100' ml. of benzene. The mixtureis filtered and the filtrate is concentrated under reduced pressure.Ethyl ether and petroleum ether is added to the oily residue and thepale yellow crystalline product is isolated by filtration.

EXAMPLE XXIII Preparation of 2( [a-cyano-a-methyl-(3,4-dimethylbenzyl)amin)acezamide A mixture of 124 ml. of anhydrous methanol, 36.7 g. of3', 4'-dimethylacetophenone, 12.8 g. of granular sodium cyanide and 39.2g. of 76% glycinarnide hydrochloride is stirred *for 18 hours at 25 30C. in a closed flask. The mixture is heated at 60 C. for 6 hours, thencooled to 30 C. and filtered. Concentration of the filtrate underreduced pressure gives an oily residue to which is added 300 ml. ofbenzene. The mixture is filtered and the filtrate is concentrated underreduced pressure. To the oily residue is added diethyl ether. The paleyellow crystalline product, melting point 8593 C., is isolated byfiltration.

EXAMPLE XXIV Preparation of 2-( [a-cyano-a-methyl- (m-cz,a,a-

trifluoromethy lbenzyl ]amin0 acetam'ide A mixture of 124 ml. ofanhydrous methanol, 46.5 g. of m-a,a,a-trifiuoromethyla-cetophenione,12.8 g. of granular sodium cyanide and 39.2 g. of 76.6% glycinamidehydrochloride is stirred for 18 hours 'at 25-30 C. in a closed flask.The mixture is heated at 60 C. for 6 hours, then cooled to 30 C. andfiltered. Concentration of the filtrate under reduced pressure gives anoily residue to 14) which is added 300 ml. of benzene. The mixture isfiltered and the filtrate is concentrated under reduced pressure. To theoily residue is added diethyl ether. The off-white crystalline product,melting point 114119 C. is isolated by filtration.

We claim: 1. A compound of the formula:

R4 R1 R NHCH2R2 References Cited by the Examiner UNITED STATES PATENTS2,786,836 3/1957 Skinner et a1 260-558 WALTER A. MODANCE, PrimaryExaminer.

N. TROUSOF, Assistant Examiner.

1. A COMPOUND OF THE FORMULA: